FAS (CD95) Mutations Are Rare in Gastric MALT Lymphoma but Occur More Frequently in Primary Gastric Diffuse Large B-Cell Lymphoma

Abstract

A loss of FAS (CD95) function has been proposed to constitute an important step in early mucosa-associated lymphoid tissue (MALT) lymphoma development and FAS mutations have been recognized in malignant lymphomas, in particular at extranodal sites. Since primary gastric lymphomas frequently exhibit resistance to FAS-mediated apoptosis, we investigated whether FAS is mutated in 18 gastric MALT lymphomas and 28 diffuse large B-cell lymphomas (DLBCL). We detected seven mutations in five lymphomas, one MALT lymphoma and four DLBCL; two DLBCL had two mutations. The MALT lymphoma exhibited a point mutation in the splice donor region of intron 3. Three DLBCL had missense mutations in exon 2, which encodes a signal peptide and a portion of the extracellular FAS ligand-binding domain. One DLBCL carried a point mutation in the splice donor region of intron 8, which would result in exon skipping. Two DLBCL harbored a missense mutation in exon 9, which encodes the intracellular death domain. The two death domain mutations inhibited FAS ligand-induced apoptosis in a dominant-negative mode, when transiently expressed in human T47D breast carcinoma and Jurkat T cells. A signal peptide and an extracellular domain mutation, however, failed to inhibit apoptosis in these transfection assays. They are likely to reduce apoptosis in lymphoma cells solely by a loss of function. In summary, our data show that FAS mutations are rare in primary gastric MALT lymphomas (5.6%) but occur in a subset of primary gastric DLBCL (14.3%) and suggest that these mutations contribute to the pathogenesis of gastric lymphomas by rendering lymphocytes resistant to apoptosis.

Tuberin activates the proapoptotic molecule BAD

“…In the past, this approach has been used to analyse the apoptotic effects of a variety of different genes (see e.g. Wohlfart et al, 2004). Besides other detections of apoptosis, we have also chosen this type of experiments, because the report showing that p70S6K regulates apoptosis via BAD Ser136 phosphorylation also made use of this approach (Harada et al, 2001).…”

The Ubiquitin E3 Ligase Cbl-b in T Cells Tolerance and Tumor Immunity

“…Furthermore, inappropriate activation of T cells in the absence of co-stimulation results in clonal anergy. 33 Intrinsic tumor escape also includes alterations that affect tumor recognition by immune effector cells such as downregulation of the peptide MHC-I complex 34 or from defects in death-receptor signaling pathways, 35 or overexpression of anti-apoptotic molecules in the tumor cells. 36,37 Human tumors arising in immuno-competent hosts have most likely already evaded immune control and therefore therapeutic strategies are required to improve the immune response against those tumor variants.…”

Ras mediates cell survival by regulating tuberin

“…Luciferase activities are indirect indicators for apoptosis. In cell populations with more luciferase activity in the lysates, more cells are viable and less apoptosis is present (see for example, Harada et al, 2001;Wohlfart et al, 2004;Freilinger et al, 2006). Ras-mediated cell survival was also detectable performing luciferase assays (Figure 1e).…”